Study Evaluated VA Population with High
Incidence of Co-Morbidities
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced the presentation of findings from a
retrospective database analysis of patients with chronic hepatitis
C virus (HCV) infection who were administered ZEPATIER® in the U.S.
Department of Veterans Affairs (VA) healthcare system. For the
evaluable population (n=2,436), 95.6 percent of veterans treated
with ZEPATIER achieved the primary outcome of sustained virologic
response (SVR), defined as undetectable HCV RNA at least twelve
weeks after the end of treatment. For patients with no HCV RNA
measurements at or after 12 weeks (19% of the study cohort), the
analysis used HCV RNA measurements available at least four and less
than 12 weeks after the end of treatment. The response rates in the
real-world setting of the VA supplement the overall findings from
the controlled clinical studies of ZEPATIER. These findings will be
presented today in an oral session (abstract #PS-095) at The
International Liver Congress™ 2017 being held in Amsterdam, the
Netherlands.
In the United States, ZEPATIER is indicated for the treatment of
chronic HCV GT1 or GT4 infection in adults. ZEPATIER is indicated
for use with ribavirin (RBV) in certain patient populations. The
U.S. Prescribing Information for ZEPATIER includes a Boxed Warning
about the risk of hepatitis B virus (HBV) reactivation in patients
co-infected with HCV and HBV. In controlled clinical studies of
ZEPATIER, SVR was the primary endpoint defined as HCV RNA less than
lower limit of quantification (LLOQ) at 12 weeks after the
cessation of treatment (SVR12).
“U.S. veterans are three times more likely to have chronic
hepatitis C compared to the general U.S. population and a high
proportion suffer co-morbid conditions that can make treatment
challenging,” said Jennifer Kramer, investigator, Michael E.
DeBakey VA Medical Center, Houston, Texas, and assistant professor
of medicine, department of medicine, Baylor College of Medicine.
“This study shows that chronic hepatitis C antiviral treatment can
result in a high rate of sustained virologic response in U.S.
veterans.”
This retrospective database analysis included patients with
chronic HCV treated with ZEPATIER (elbasvir and grazoprevir) in the
VA healthcare system between February 1, 2016 and August 1, 2016.
Study outcomes include real-world utilization and SVR rates. Please
see additional information about the design, methodology and
limitations of this observational study below.
After applying study exclusion criteria, 2,436 patients were
included in the evaluable population cohort. The mean age of
subjects was 63.5 years. The prevalence of co-morbidities as
determined by ICD-9 and CPT codes as recorded in the VA database
was as follows: cirrhosis (33.2%), diabetes (53.2%), depression
(57.2%) and HIV co-infection (3%). Additionally, more than half of
the patients had a history of drug (53.9%) or alcohol (60.5%)
abuse. The population included 1,988 previously untreated patients
and 448 treatment-experienced patients (322 of whom previously
received an interferon-based regimen with or without an NS3/4A HCV
protease inhibitor, and 126 of whom previously received an
interferon-free direct-acting antiviral regimen).
A total of 95.6 percent (2,328/2,436) of patients in the
evaluable population achieved SVR following treatment with
ZEPATIER. The SVR rates by genotype (GT) were as follows: all GT1,
95.4 percent (2218/2324); GT1a, 93.4 percent (788/844); GT1b, 96.6
percent (1379/1428); and GT4, 96.9 percent (62/64). The SVR rates
by baseline viral load (BVL) were as follows: BVL greater than
800,000 IU/ml, 94.7 percent (1497/1580); and BVL less than or equal
to 800,000 IU/ml, 97.3 percent (726/746).
The SVR rates by baseline patient characteristics were as
follows: male, 95.5 percent (2,245/2,350); female, 96.5 percent
(83/86); African American, 95.9 percent (1,342/1,400); Hispanic,
95.1 percent (77/81); White, 95.0 percent (783/824); previously
untreated, 96.1 percent (1,910/1,988); treatment-experienced, 93.3
percent (418/448); cirrhosis, 95.5 percent (772/808); without
cirrhosis, 95.6 percent (1556/1628); stage 3 chronic kidney disease
(CKD) (eGFR 30 to 59 mL/min/1.73m2), 96.7 percent (380/393); stage
4-5 CKD (eGFR less than 30 mL/min/1.73m2), 96.3 percent (392/407);
HIV positive, 98.6 percent (73/74); HIV negative, 95.5 percent
(2255/2362); history of alcohol abuse, 95.9 percent (1412/1473); no
history of alcohol abuse, 95.1 percent (916/963); history of drug
abuse, 95.3 percent (1251/1313); no history of drug abuse, 95.9
percent (1077/1123).
Adverse event data were not collected as part of this real-world
data analysis.
“Analysis of data from real-world medical settings can provide
useful insights to supplement knowledge gained from randomized
clinical trials,” said Susan Shiff, senior vice president, center
for observational and real-world evidence, Merck. “These data from
a real-world VA setting add to the body of evidence on ZEPATIER
(elbasvir and grazoprevir) and help deepen scientific understanding
of the treatment of this complex disease affecting diverse,
sometimes difficult to treat, patient populations.”
Study Methodology
Patients with chronic HCV treated with ZEPATIER from February 1
to August 1, 2016 were identified from the VA Corporate Data
Warehouse, a national repository of VA electronic medical records.
Inclusion criteria specified initiation of ZEPATIER therapy, at
least 18 years of age, positive HCV RNA, and at least one inpatient
or outpatient visit within a one-year period prior to treatment
initiation (n=2,985). Patients were excluded if they had RBV added
greater than one month after treatment initiation (n=23). Patients
without SVR data or on-treatment HCV RNA data (n=494), or those
treated with ZEPATIER for greater than seventeen weeks (n=32), were
excluded as well. The total number of patients in the evaluable
population was 2,436.
SVR was assessed based on undetectable HCV RNA at least twelve
weeks after the end of treatment. For patients with no HCV RNA
measurements at or after 12 weeks, the analysis used HCV RNA
measurements available at least four and less than 12 weeks after
the end of treatment. SVR was evaluated based on HCV RNA
measurement at least 12 weeks post treatment in 81 percent of the
study population.
About Real-World Data Analyses and Associated
Limitations
Real-world studies analyze data generated outside of randomized
clinical trials, such as through analyses of electronic medical
records or claims databases, to provide insight into how medicines
perform or are used from a clinical and economic viewpoint in
real-world clinical settings. Information from real-world analyses
alone does not provide sufficient evidence to validate efficacy or
safety of a therapeutic regimen and does not provide a substitute
for evidence obtained from randomized controlled clinical
trials.
This study is subject to certain limitations. The VA population
may not be generalizable to the entire U.S. population, due in part
to the potential for a differing demographic make-up and/or risk
factors. Bias may exist as diagnoses and co-morbidities were
identified through ICD-9 and CPT codes. Treatment completion was
identified through prescription records which may not reflect
adherence. Database analyses are also prone to errors in coding and
missing data, including unavailable SVR data at or after the
12-week post-treatment time point. Additionally, some laboratory
data including data on the presence of baseline NS5A resistance
associated substitutions was not available at the time of this
analysis.
About the VA Corporate Data Warehouse (CDW)
The Department of Veterans Affairs Veterans Healthcare
Administration (VHA) is supported by one of the largest integrated
healthcare information systems in the United States. The VHA's
Corporate Data Warehouse (CDW) was developed in 2006 to accommodate
the massive amounts of data being generated from more than 20 years
of use and to streamline the process of knowledge discovery to
application.
About ZEPATIER® (elbasvir and grazoprevir)
50mg/100mg Tablets
ZEPATIER is a fixed-dose combination product containing
elbasvir, a HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A
protease inhibitor. In the United States, ZEPATIER is indicated for
the treatment of chronic HCV GT1 or 4 infection in adults. ZEPATIER
is indicated for use with ribavirin (RBV) in certain patient
populations. The efficacy of ZEPATIER has not been established in
patients who have previously failed treatment with other regimens
that included an NS5A inhibitor.
Selected Safety Information about ZEPATIER
The US Prescribing Information for ZEPATIER contains a Boxed
Warning about the risk of hepatitis B virus (HBV) reactivation in
patients coinfected with HCV and HBV. Healthcare professionals
should test all patients for evidence of current or prior HBV
infection by measuring hepatitis B surface antigen (HBsAg) and
hepatitis B core antibody (anti-HBc) before initiating treatment
with ZEPATIER. HBV reactivation has been reported in HCV/HBV
coinfected patients who were undergoing or had completed treatment
with HCV direct-acting antivirals and were not receiving HBV
antiviral therapy. Some cases have resulted in fulminant hepatitis,
hepatic failure, and death. Healthcare professionals should monitor
HCV/HBV coinfected patients for clinical and laboratory signs of
hepatitis flare or HBV reactivation during HCV treatment and
post-treatment follow-up. Healthcare professionals should initiate
appropriate patient management for HBV infection as clinically
indicated.
HBV reactivation has been reported in HBsAg positive patients
and also in patients with serologic evidence of resolved HBV
infection (ie, HBsAg negative and anti-HBc positive). The risk of
HBV reactivation may be increased in patients receiving some
immunosuppressant or chemotherapeutic agents. HBV reactivation is
characterized as an abrupt increase in HBV replication manifesting
as a rapid increase in serum HBV DNA level. In patients with
resolved HBV infection, reappearance of HBsAg can occur.
Reactivation of HBV replication may be accompanied by hepatitis,
ie, increases in aminotransferase levels and, in severe cases,
increases in bilirubin levels, liver failure, and death can
occur.
ZEPATIER (elbasvir and grazoprevir) is not for use in patients
with moderate or severe hepatic impairment (Child Pugh B or C).
ZEPATIER is also not for use with inhibitors of organic anion
transporting polypeptides 1B1/3 (OATP1B1/3) that are known or
expected to significantly increase grazoprevir plasma
concentrations (e.g., atazanavir, darunavir, lopinavir, saquinavir,
tipranavir, cyclosporine), strong cytochrome P450 3A (CYP3A)
inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s
Wort), and efavirenz. If ZEPATIER (elbasvir and grazoprevir) is
administered with RBV, healthcare professionals should refer to the
prescribing information for RBV as the contraindications, warnings
and precautions, adverse reactions and dosing for RBV also apply to
this combination regimen.
Elevations of alanine transaminase (ALT) to greater than 5 times
the upper limit of normal (ULN) occurred in 1% of subjects,
generally at or after treatment week 8. These late ALT elevations
were typically asymptomatic and most resolved with ongoing or
completion of therapy. Healthcare professionals should perform
hepatic lab testing on patients prior to therapy, at treatment week
8, and as clinically indicated. For patients receiving 16 weeks of
therapy, additional hepatic lab testing should be performed at
treatment week 12.
Patients should be instructed to consult their healthcare
professional without delay if they have onset of fatigue, weakness,
lack of appetite, nausea and vomiting, jaundice or discolored
feces. Healthcare providers should consider discontinuing ZEPATIER
(elbasvir and grazoprevir) if ALT levels remain persistently
greater than 10 times ULN. ZEPATIER should be discontinued if ALT
elevation is accompanied by signs or symptoms of liver inflammation
or increasing conjugated bilirubin, alkaline phosphatase, or
international normalized ratio.
The concomitant use of ZEPATIER with certain drugs may lead to
adverse reactions or reduced therapeutic effect due to drug
interactions. Certain strong CYP3A inhibitors may increase the
plasma concentration of ZEPATIER, leading to possibly clinically
significant adverse reactions. Moderate CYP3A inducers may decrease
the plasma concentration of ZEPATIER, leading to reduced
therapeutic effect and possible development of resistance.
Coadministration of ZEPATIER with these drugs is not recommended.
Physicians should consult the Prescribing Information for potential
drug interactions.
In subjects receiving ZEPATIER for 12 weeks, the most commonly
reported adverse reactions of all intensity (greater than or equal
to 5% in placebo-controlled trials) were fatigue, headache and
nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the
most commonly reported adverse reactions of moderate or severe
intensity (greater than or equal to 5%) were anemia and
headache.
Selected Dosage and Administration Information for
ZEPATIER® (elbasvir and grazoprevir)
ZEPATIER is a single tablet taken once daily. The recommended
dosing is 12 or 16 weeks with or without RBV, depending on HCV
genotype, prior treatment history and, for patients with genotype
1a infection, presence of certain baseline NS5A
resistance-associated polymorphisms. See Prescribing Information
for ZEPATIER for specific dosage regimens and durations. Refer to
RBV prescribing information for RBV dosing and dosage modifications
when ZEPATIER is given with RBV. To determine dosage regimen and
duration of ZEPATIER for genotype 1a patients, testing for the
presence of virus with one or more baseline NS5A
resistance-associated polymorphisms at positions 28, 30, 31, or 93
is recommended prior to initiating treatment.
Merck’s Commitment to HCV
For more than 30 years, Merck has been at the forefront of the
response to the HCV epidemic. Merck’s chronic HCV clinical
development programs have included more than 135 clinical trials in
approximately 40 countries and have enrolled nearly 10,000
participants. As part of our longstanding leadership in infectious
diseases, Merck collaborates with the scientific and patient
communities to develop and deliver innovative solutions to support
people living with chronic HCV worldwide.
About Merck
For more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been bringing forward medicines and vaccines for
many of the world's most challenging diseases. Through our
prescription medicines, vaccines, biologic therapies and animal
health products, we work with customers and operate in more than
140 countries to deliver innovative health solutions. We also
demonstrate our commitment to increasing access to health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer's disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us
on Twitter, Facebook, Instagram, YouTube
and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
If underlying assumptions prove inaccurate or risks or
uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2016
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see Prescribing Information for ZEPATIER (elbasvir and
grazoprevir) at
http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf
and the Patient Information for ZEPATIER at
http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_ppi.pdf
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